EP0937069B1 - Piperazinoderivate als neurokinin-antagonisten - Google Patents

Piperazinoderivate als neurokinin-antagonisten Download PDF

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EP0937069B1
EP0937069B1 EP97912827A EP97912827A EP0937069B1 EP 0937069 B1 EP0937069 B1 EP 0937069B1 EP 97912827 A EP97912827 A EP 97912827A EP 97912827 A EP97912827 A EP 97912827A EP 0937069 B1 EP0937069 B1 EP 0937069B1
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compound
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substituted
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formula
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EP0937069A1 (de
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David J. Blythin
Xiao Chen
Richard J. Friary
Kevin D. Mccormick
John J. Piwinski
Neng-Yang Shih
Ho-Jane Shue
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Merck Sharp and Dohme Corp
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Schering Corp
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    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to a genus of compounds useful as antagonists of neurokinin receptors.
  • these can be neurokinin-1 receptor (NK 1 ) antagonists.
  • NK 1 neurokinin-1 receptor
  • NK 2 neurokinin-2 receptor
  • Some can also be neurokinin-2 receptor (NK 2 ) antagonists.
  • Some can also be neurokinin-3 receptor (NK 3 ) antagonists.
  • Neurokinin receptors are found in the nervous system and the circulatory system and peripheral tissues of mammals, and therefore are involved in a variety of biological processes. Neurokinin receptor antagonists are consequently expected to be useful in the treatment or prevention of various mammalian disease states, for example pulmonary disorders like asthma, cough, bronchospasm, chronic obstructive pulmonary diseases, and airway hyperreactivity; skin disorders and itch, for example, atopic dermatitis, and cutaneous wheal and flare; neurogenic inflammation inflammatory diseases such as arthritis, migraine, nociception; CNS diseases such as anxiety, emesis, Parkinson's disease, movement disorders and psychosis; convulsive disorders, renal disorders, urinary incontinence, ocular inflammation, inflammatory pain, and eating disorders such as food intake inhibition; allergic rhinitis, neurodegenerative disorders, psoriasis, Huntington's disease, depression, and various gastrointestinal disorders such as Crohn's disease.
  • pulmonary disorders like asthma, cough, bronchospasm,
  • NK 1 receptors have been reported to be involved in microvascular leakage and mucus secretion
  • NK 2 receptors have been associated with smooth muscle contraction, making NK 1 and NK 2 receptor antagonists especially useful in the treatment and prevention of asthma.
  • NK 3 receptor antagonists are especially useful in the treatment and prevention of asthma, inflammatory diseases and conditions, such as ocular inflammation, allergic rhinitis, cutaneous wheal and flare, psoriasis, atopic dermatitis, CNS diseases such as anxiety and Parkinson's disease.
  • each R a and R b is independently selected from the group consisting of H, C 1 -C 6 alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl and allyl; or when R a and R b are attached to the same nitrogen, then R a and R b , together with the nitrogen to which they are attached, can form a 4 to 7 member ring; each R 1 and R 2 is independently selected from the group consisting of H, C 1 -C 6 alkyl, -CF 3 , -C 2 F 5 , Cl, Br, I, F, -NO 2 , -OR a , -CN, -NR a R b , -SR a , and provided R a is not H in or or when R 1 and R 2 are on adjacent carbons on a ring, they can form wherein n' is 1 or 2; each R 3 is independently selected from the group consisting of H, C 1 -C 6 alkyl, phen
  • G is not or any enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof.
  • Preferred compounds of the invention are compound of formula I wherein R e and R f are H, R 6 is
  • R g is where R a is not H
  • Exemplary compounds of the invention are compounds of the formulas: wherein G' is represented by the following formulas: compounds of the formulas wherein G" and G''' are selected from the group consisting of: wherein R 6 ' is selected from the group consisting of: or G'' and G''' are selected from the group consisting of: wherein R m ' is selected from the group consisting of: and wherein G" is also selected from the group consisting of: and wherein G''' is also selected from the group consisting of: and compounds of the formula wherein R 6 ' is as defined above and wherein Ar' is selected from the group consisting of: or any stereoisomer therof, including any enantiomer, diastereomer, endo, exo, R or S form thereof, or a pharmaceutically acceptable salt thereof.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a thereapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier.
  • the invention also relates to a method for inducing neurokinin antagonism which comprises administering a neurokinin antagonistic effective amount of a compound of the invention to a mammal in need thereof.
  • the invention also relates to a method for treating chronic airway diseases such as asthma and allergies; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositos, osteoarthritis, and rheumatoid arthritis; migraine; central nervous system disorders such as emesis, depression, psychosis, dementia, and Alzheimer's disease; Down's syndrome; neuropathy: multiple sclerosis; ophthalmic disorders; conjunctivitis; auto immune disorders; graft rejection; systemic lupus erythematosus; GI disorders such as Crohn's disease and ulcerative colitis; disorders of bladder function; circulatory disorders such as angina; Raynaud's disease; coughing and pain.
  • the invention also relates to a method of treating asthma which comprises administering to a mammal in need of such treatment an anti-asthma effective amount of a compound of the invention for such purpose.
  • alkyl means a straight or branched, saturated hydrocarbon chain having from 1 to 6 carbon atoms. The number of carbon atoms may be designated.
  • C 1 -C 6 alkyl represents a straight or branched, saturated hydrocarbon having from 1 to 6 carbon atoms.
  • C 3 -C 6 cycloalkyl means a cycloalkyl having from 3 to 6 carbon atoms, that is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • alkenyl means means a straight or branched, saturated alkenyl having from 2 to 6 carbon atoms. The number of carbon atoms may be designated.
  • C 2 -C 6 alkenyl represents a straight or branched alkenyl having from 1 to 6 carbon atoms.
  • alkynyl means a straight or branched alkynyl having from 2 to 6 carbon atoms. The number of carbon atoms may be designated.
  • C 2 -C 6 alkynyl represents a straight or branched chain alkynyl having from 2 to 6 carbon atoms.
  • a heavy dark line ( ) denotes a chemical bond coming above the plane of the page.
  • a dashed line ( ) denotes a chemical bond coming below the plane of the page.
  • R 1 , R 2 , and R 3 can be in either of the rings of the above naphthyl moiety.
  • compounds of the invention include stereoisomers, i.e., enantiomers, diastereomers, endo and exo forms.
  • Enantiomers may be separated, where appropriate, by derivatization or salt formation with an optically pure reagent, followed by separation by one of the aforementioned methods. Alternatively, enantiomers may be separated by chromatography on a chiral support.
  • the compounds of the invention canexist in unsolvated as well as Solvated forms, including hydrated forms, e.g. the hemihydrate.
  • the solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like are equivalent to the unsolvated forms for the purposes of the invention.
  • Those compounds of the invention which contain a basic group such as -CH 2 NH 2 form pharmaceutically acceptable salts.
  • the preferred pharmaceutically acceptable salts are nontoxic acid addition salts formed by adding to a suitable compound of the invention about a stoichiometric amount of a mineral acid, such as HCl, HBr, H 2 SO 4 or H 3 PO 4 or of an organic acid such as acetic, propionic, valeric, oleic, palmitic, stearic, lauric, benzoic, lactic, para-toluenesulfonic, methanesulfonic, citric, maleic, fumaric, succinic, hydroxypropane sulfonic and the like, respectively.
  • a mineral acid such as HCl, HBr, H 2 SO 4 or H 3 PO 4
  • organic acid such as acetic, propionic, valeric, oleic, palmitic, stearic, lauric, benzoic, lactic, para
  • RT room temperature.
  • variables in the structural formulas below are as defined above. Starting materials and reagents used in the methods and examples below, are known or may be prepared according to known methods.
  • substituted phenyl means wherein R 1 , R 2 , and R 3 are as described herein.
  • Substituted means substituted bv R 1 , R 2 , and/or R 3 as described herein ie substituted benzyl, substituted aryl and substituted heteroaryl.
  • Aryl means phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl or fluorenyl.
  • Halogeno refers to fluoro, chloro, bromo or iodo atoms.
  • Heterocycloalkyl refers to 4- to 6-membered rings comprising 1 to 3 heteroatoms independently selected from the group consisting of -O-, -S- and -N(R 6 )-, with the remaining ring members being carbon.
  • heterocycloalkyl rings are tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl.
  • Examples of single-ring heteroaryl groups are pyridyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, thiadiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazolyl.
  • benzofused heteroaryl groups are quinolinyl, thianaphthenyl (i.e., benzothienyl) and benzofurazanyl. N-oxides of nitrogen-containing heteroaryl groups are also included. All positional isomers are contemplated, e.g., 1-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.
  • R 2 and R 3 substituents form a ring and additional heteroatoms are present, the rings do not include adjacent oxygen and/or sulfur atoms or three adjacent heteroatoms.
  • Typical rings so formed are morpholinyl, piperazinyl and piperidinyl.
  • BOC means t-butoxycarbonyl
  • Ph phenyl
  • parallel synthesis means the preparation of individual chemical compounds as one of a batch of, for instance, 20, 30, or even 100 identical reactions on usually a single substrate but using a different reagent in each vessel.
  • Such reagents are always of the same general class- in this case, either carboxylic acids or organic amines in any set of parallel reactions.
  • the conditions used for each reaction are identical to those described in the examples , except that a simplified work-up is employed, generally a simple wash either with acid or base if appropriate, then water.
  • the presence of the product is detected by thin layer chromatography (TLC) using known products as representative standards. Further characterization by combination HPLC/MS is generally performed. No further purification is performed on these materials before they are submitted to biological assays.
  • TLC thin layer chromatography
  • each R c and R c' is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, unsubstituted or substituted phenyl, and unsubstituted or substituted benzyl.
  • the starting materials in the methods below are either known or can be prepared in accordance with known methods.
  • the following compounds are either known or can be prepared in accordance with known methods: the diamine A, the compounds of formulas A, VI. VIII, X, XI, XIV, XVIII, XIX, XXa, A', XXV, and Z-H, as well as esters of formula XI, and compounds of formula Method 1 .
  • the group Ar 2 is an aromatic group with no I or Br substituents, then the following method may be used to prepare the useful intermediates (IV):
  • Ar 2 has no halo substituents
  • reduction of a compound of formula II' by catalytic hydrogenation using, for instance, palladium acetate, preferably in acetic acid solvent, results in preferential reduction of the pyrazine ring, leaving the aromatic ring unreduced, that is, it results in a compound of formula II.
  • 10% Pd on charcoal can be used in an alcohol solvent, preferably methanol, with or without the addition of a small quantity (1 to 5 equivalents) of acetic acid. Reaction times of about 1 to 24 hours generally suffice for this reaction, which is preferentially run at room temperature or slightly above (up to about 50°C) and using from 1 to about 6 atmospheres pressure of hydrogen.
  • the intermediate of formula II may also be prepared from a compound of formula II', even if the group Ar 2 contains halogen atoms, by reduction using a strong hydride ion donor, preferably lithium aluminum hydride (LAH) or diisobutyl aluminum hydride (DIBAL-H) in an ether solvent, such as ether, THF or dimethoxyethane (DME).
  • a strong hydride ion donor preferably lithium aluminum hydride (LAH) or diisobutyl aluminum hydride (DIBAL-H) in an ether solvent, such as ether, THF or dimethoxyethane (DME).
  • the group Ar 2 contains one or more halogen atoms on an aromatic ring and the other groups are as in Method 1, then an alternate route to a compound of formula IV is preferred.
  • this method can be used to prepare compounds in which I is from 0 to 2.
  • R c can be bound to any position between the two nitrogens.
  • R c can be bound to any available cyclic position that is occupied by carbon, and that is between the two nitrogens.
  • Suitable conditions for this type of reaction include the use of an alcohol solvent, preferably methanol, or 2,2,2-trifluoroethanol, made slightly acidic with a weak organic acid, such as acetic acid, and a reducing agent known to favor reductive amination reactions, preferably sodium cyanoborohydride, NaBH 3 CN.
  • an alcohol solvent preferably methanol, or 2,2,2-trifluoroethanol
  • a weak organic acid such as acetic acid
  • a reducing agent known to favor reductive amination reactions preferably sodium cyanoborohydride, NaBH 3 CN.
  • Standard coupling techniques may be applied, an example being the use of N-hydroxybenztriazole (HOBT) and a water-soluble carbodiimide, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (DEC), in a non-hydroxylic solvent such as CH 2 Cl 2 , DMF or a mixture of the two foregoing solvents.
  • HOBT N-hydroxybenztriazole
  • DEC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
  • the reaction is run, preferably, at or below RT, and takes from 1 to 40 hours for completion, depending upon the substrates.
  • a suitable base for cyclization is the alkali metal salt of an alcohol in the alcohol itself used as solvent.
  • a solution of sodium ethoxide in ethanol may be used.
  • the temperature is preferably around RT but may be slightly above or below, in the range 0°C to about 40°C.
  • the reaction is generally complete within a few hours. Suitable reaction times are from 1 to 24 hours.
  • Reduction of the diketopiperazine of formula XIII to a compound of formula II may be accomplished preferentially with a strong hydride reducing agent, such as LAH or a solution of sodium bis(2-methoxy-ethoxy)aluminum hydride in toluene (also known as Red-Al®), or the BH 3 .S(CH 3 ) 2 complex.
  • a strong hydride reducing agent such as LAH or a solution of sodium bis(2-methoxy-ethoxy)aluminum hydride in toluene (also known as Red-Al®), or the BH 3 .S(CH 3 ) 2 complex.
  • Suitable solvents for this reaction are DME and other higher boiling ethers since the reaction is run at elevated temperatures, from about 50°C to about 110°C, preferably about 90°C:
  • L is any readily available ester residue such as C 1 -C 7 alkyl, more preferably methyl or ethyl.
  • a compound of formula II may be converted to a compound of formula IV by the processes described in Method 1 above or Method 6 below.
  • Method 4. The intermediates of formula IV or IVA, formed via any of the previous methods, may be further processed as follows.
  • a compound of formula IVA will be used in the Schemes. Reaction of a compound of formula IVA with an activated halo-acid, generally the acid halide of formula XIV, in which Hal represents Cl, Br, or I, yields the acylated derivative of formula XV that is, m is 1.
  • An organic base is used to take up the hydrogen halide formed in the reaction, suitable bases being triethylamine (TEA) and Hünig's Base.
  • Suitable reaction media include halogenated solvents, such as methylene chloride and chloroform.
  • the reaction is preferably run at low temperature, at least initially. Suitable temperatures are in the region of -50°C down to -80°C. Later in the reaction it may be desirable to allow the mixture to warm up to about RT to ensure completion of the reaction.
  • Suitable reducing agents to effect this transformation include the borane-dimethyl sulfide complex, as well as other less selective reagents, such as LAH, (assuming that no other group reactive to LAH is present), Red-Al®, and diborane in ether.
  • Effective temperatures for the borane-dimethylsulfide complex to reduce compounds of formula XVI range from RT to the reflux temperature of the solution of the reagent in THF (about 80°C).
  • Method 6 Intermediates of the formula XVIII may be selectively acylated by coupling with an acid of the formula XIX.
  • Standard coupling techniques may be applied, for example the use of HOBT, a water-soluble carbodiimide, such as DEC, and an organic base, such as Et 3 N, in a non-hydroxylic solvent, such as CH 2 Cl 2 , at a temperature of about -20°C initially.
  • HOBT a water-soluble carbodiimide
  • DEC a water-soluble carbodiimide
  • Et 3 N an organic base
  • CH 2 Cl 2 a non-hydroxylic solvent
  • the product of reaction is the amide of formula XX.
  • Compounds of the formula XX may be further acylated using an acid halide of formula XIV.
  • the reaction is run, preferably at about -78°C, over a period of 1 to 12 hours, in a halogenated solvent, such as methylene chloride or similar solvent.
  • a halogenated solvent such as methylene chloride or similar solvent.
  • An organic tertiary amine is used to absorb the H-Hal produced in the reaction. Suitable amines include triethylamine and Hünig's Base.
  • Hal means Cl, Br, or I.
  • the compounds of formula XXI may be used for further reaction without isolation.
  • Additional organic base for instance, Hünig's Base, is added to the mixture followed by Z-H, at or around -78°C. The reaction is completed by allowing the mixture to warm to RT overnight yielding the compounds of formula XXII after work-up and purification by standard methods.
  • the reaction of Z-H with XXI is preferably carried out after isolation of XXI by adding NaH, or a similar base, to a solution of Z-H (wherein X 4 is -O-) in an ether solvent (e.g., THF) at or near RT, under N 2 .
  • a solvent such as THF
  • XXI in a solvent such as THF is added and the mixture is allowed to stir at RT for 2 to 24 hours, followed by work-up and purification by flash chromatography to obtain the product of formula XXII wherein X 4 is -O-.
  • Suitable reducing agents to effect this transformation include the borane-methyl sulfide complex, as well as other less selective reagents, such as LAH, Red-Al®, and diborane in ether or other unreactive solvents, such as THF.
  • THF unreactive solvents
  • Some of the substrates Z-H for the alkylation reaction were synthesized from diamino compound (A) by initial conversion to the t-BOC protected derivative(B) followed by removal of the benzyl group by hydrogenolysis over a suitable catalyst such as Pd(OH) 2 to yield the t-BOC protected derivative (C). Subsequent elaboration of (C) can be accomplished by either alkylation or reductive alkylation depending on the availability of reagents for these reactions.
  • the same product, (Ea) may be prepared from (C) by alkylation with the halide derivative (G) in which "Hal” is Cl, Br, or I.
  • halide derivative (G) in which "Hal” is Cl, Br, or I.
  • Other activated leaving groups are also possible for this reagent , such as mesylates or tosylates.
  • the reagent is preferably primary but the reaction can also often be made to work acceptably for secondary derivatives.
  • the product of the alkylation, (Ea), may be treated as described above to produce the reagent (Fa) which represents one of the preferred forms of Z which can be used to convert a compound of formula XXI to a compound of formula XXII.
  • the intermediate (C) (below) may also be modified by acylation, for instance with an acid halide of formula (H), to produce the intermediate (I), in which n 3 ⁇ 0. Removal of the BOC protecting group, as described previously, leads to the amine (J) which represents one of the preferred forms of Z. This may be used to convert a compound of formula (XXI) to a compound of the invention, as described above.
  • the starting material for this process is the N-BOC protected amine (M) which may be converted to (L) by standard techniques involving formation of the oxime using hydroxylamine hydrochloride in pyridine followed by reduction with hydrogen over Raney nickel in ethanol solution. Removal of the protecting group from (K), under conditions described previously, results in the amine (N).
  • the starting material (N) is provided as a salt, such as the HCl salt.
  • a salt such as the HCl salt.
  • an organic tertiary base such as Hünig's base
  • Alkylation of (N) may be accomplished with a suitable halogen-containing reagent, for instance, to produce (Q).
  • a suitable halogen-containing reagent for instance, to produce (Q).
  • Reagents such as (G) may be used for this conversion.
  • one of the -C(R e )(R f )- groups may be a carbonyl group with the exception that the carbon in the carbonyl can not be directly attached to the nitrogen atom since these products are amides which are described above.
  • a reductive alkylation reaction may be performed, as described previously, to produce the compound of the invention (R).
  • the process to conduct this conversion is the same as described in Method 6 for conversion of a compound of formula XXII to a compound of formula XXIII.
  • the reagent of preference is the borane-methyl sulfide complex.
  • a compound of formula IVA can be converted to a target compound of formula XVI as described previously.
  • reaction occurs preferentially at the nitrogen atom further away from the Ar 2 group.
  • Reaction of this intermediate with a reagent of structure (XIV) as described above, leads to the halo-derivative (XXIX).
  • Suitable reagents include trifluoroacetic acid and HCl.
  • a method for introducing a group, R c , into the sidechain of a compound of the invention begins with a previously prepared compound of formula (XX). This may be coupled with a suitably protected amino-acid derivative of formula (XXXII) in which the t-BOC group is used as a representative protecting group.
  • a relatively reactive coupling agent such as BOP-Cl of formula (XXXIII)
  • BOP-Cl of formula (XXXIII) is preferred and the reaction is run under standard coupling conditions well known to one skilled in the art. Suitable conditions include the use of CH 2 Cl 2 and/or DMF as solvent, with triethylamine or Hünig's Base, and a temperature between 0°C initially and RT. Usual work-up conditions yield the protected intermediate of formula (XXXIV).
  • a group Z wherein X 4 is -NHR 5 in the final product, can be introduced into the molecule using an aldehyde or ketone in which the aforementioned group is present at the carbon atom that is to be joined to the amino group of the formula (XXXV).
  • An example of such an intermediate is a compound of the formula (XXXVI). although those skilled in the art will recognize that the other Z groups claimed can be used in place of XXXVI.
  • this group becomes the Z group of the compounds of the invention, that is, the "Y-NH” group shown in compounds of the formula (XXXVII) just below is equivalent to the "Z” group shown in the Summary of the Invention.
  • Conditions for this reductive amination procedure are known in the art and are exemplified by the use of NaBH 3 CN in MeOH with the addition of several equivalents of acetic acid. Geniprally, the reaction is performed at RT and is left to react overnight.
  • Product is Isolated by standard means, such as decomposition of excess reagent with H 2 O and extraction of the product into an organic solvent such as CH 2 Cl 2 or a mixture of Et 2 O and CH 2 Cl 2 .
  • the in vitro and in vivo activity of the compounds of the invention can be determined by the following procedures.
  • Test compounds are evaluated for their ability to inhibit the activity of the NK 1 agonist Substance P on the isolated guinea pig vas deferens.
  • Freshly cut vas deferens are removed from male Hartley guinea pigs (230-350g) and suspended in 25 ml tissue baths containing Kreb's Henseleit solution warmed to 37°C and constantly aerated with 95% O 2 and 5% CO 2 . Tissues are adjusted to 0.5 g and allowed to equilibrate for a period of 30 minutes.
  • the vas deferens are exposed to an electrical field stimulation (Grass S48 Stimulator) every 60 seconds at an intensity that will cause the tissue to contract 80% of its maximum capacity.
  • Substance P potentiates the electrical field stimulated-induced contractions of the guinea pig vas deferens.
  • all tissues control or drug treated are exposed to cumulative concentrations of Substance P (1X10 -10 M - 7X10 -7 M).
  • Single log-concentrations of the test compounds are given to separate tissues and allowed to equilibrate for 30 minutes before a Substance P concentration-response curve is generated. At least 5 separate tissues are used for each control and individual drug-concentration for every drug assay.
  • Inhibition of the Substance P is demonstrated by a rightward shift of its concentration-response curve. These shifts are used to determine the pA 2 value, which is defined as the negative log of the molar concentration of the inhibitor which would require that twice as much agonist be used to elicit a chosen response. This value is used to determine relative antagonist potency.
  • Tracheal rings are suspended from transducers and anchored in 15.0 ml water jacketed organ baths by means of stainless steel hooks and 6-0 silk. Baths are filled with Krebs buffer, pH 7.4, maintained at 37°C and continuously aerated with 95% O 2 - 5% CO 2 gas. Tracheal rings are placed under 1.0 g initial tension and allowed a 90 min equilibration period with four 1 ⁇ M NKA challenge, wash and recovery cycles at 20 min intervals. 30 min vehicle pretreatment is followed by cumulative additions of rising doses of NKA (3 nM - 1 ⁇ M final concentration, 5 min intervals between additions). The final NKA response is followed by a 15 min wash and recovery period.
  • Tissue responses to NKA are recorded as positive pen displacements over baseline and converted to grams tension by comparison to standard weights. Responses are normalized as a % of the maximal tissue tension.
  • ED 50 's are calculated for NKA from the control and treated NKA dose responses and compared.
  • Test compounds resulting in an agonist dose ratio ⁇ 2 at a screening concentration of 1 ⁇ M are considered actives. Further dose response data is obtained for actives so that an apparent pA 2 estimate can be calculated.
  • mice Studies are performed on male Hartley guinea pigs ranging in weight from 400-650 g.
  • the animals are given food and water ad libitum.
  • the animals are anesthetized by intraperitoneal injection of dialurethane (containing 0.1 g/ml diallylbarbituric acid, 0.4 g/ml ethylurea and 0.4 g/ml urethane).
  • dialurethane containing 0.1 g/ml diallylbarbituric acid, 0.4 g/ml ethylurea and 0.4 g/ml urethane.
  • the jugular vein is cannulated for the injection of drugs.
  • the Evans blue dye technique (Danko, G. et al., Pharmacol. Commun. , 1, 203-209, 1992) is used to measure airway microvascular leakage (AML). Evans blue (30 mg/kg) is injected intravenously, followed 1 min later by i.v. injection of substance P (10 ⁇ g/kg). Five min later, the thorax is opended and a blunt-ended 13-guage needle passed into the aorta. An incision is made in the right atrium and blood is expelled by flushing 100 ml of saline through the aortic catheter. The lungs and trachea are removed en-bloc and the trachea and bronchi are then blotted dry with filter paper and weighed.
  • Evans blue is extracted by incubation of the tissue at 37°C for 18 hr in 2 ml of formamide in stoppered tubes. The absorbance of the formamide extracts of dye is measured at 620 nm. The amount of dye is calculated by interpolation from a standard curve of Evans blue in the range 0.5-10 ⁇ g/ml in formamide. The dye concentration is expressed as ng dye per mg tissue wet weight. Test compounds were suspended in cyclodextran vehicle and given i.v. 5 min before substance P.
  • the guinea pigs are placed inside a whole body plethysmograph and the catheters connected to outlet ports in the plethysmograph wall.
  • Airflow is measured using a differential pressure transducer (Validyne, Northridge CA, model MP45-1., range ⁇ 2 cmH 2 O) which measures the pressure across a wire mesh screen that covers a 1 inch hole in the wall of the plethysmograph.
  • the airflow signal is electrically integrated to a signal proportional to volume.
  • Transpulmonary pressure is measured as the pressure difference between the trachea and the esophagus using a differential pressure transducer (Validyne, Northridge, CA, model MP45-1, range ⁇ 20 cm H 2 O).
  • the volume, airflow and transpulmonary pressure signals are monitored by means of a pulmonary analysis computer (Buxco Electronics, Sharon, CT, model 6) and used for the derivation of pulmonary resistance (R L ) and dynamic lung compliance (C Dyn ).
  • NKA Sodium EDTA
  • Increasing iv doses of NKA are administered at half log (0.01-3 ⁇ g/kg) intervals allowing recovery to baseline pulmonary mechanics between each dose. Peak bronchoconstriction occurs within 30 seconds after each dose of agonist. The dose response is stopped when C Dyn is reduced 80-90% from baseline.
  • One dose-response to NKA is performed in each animal. Test compounds are suspended in cyclodextran vehicle and given i.v. 5 min before the initiation of the NKA dose response.
  • dose response curves to NKA are constructed by plotting the percent increase in R L or decrease in C Dyn against log dose of agonist.
  • the doses of NKA that increased R L by 100% (R L 100) or decreased C Dyn by 40% (C Dyn 40) from baseline values are obtained by log-linear interpolation of the dose response curves.
  • CHO cells transfected with the coding regions for the human neurokinin 1 (NK 1 ) of the human neurokinin 2 (NK 2 ) receptors are grown in Dulbecco's minimal essential medium supplemented with 10% fetal calf serum, 0.1 mM non-essential amino acids, 2 mM glutamine, 100units/ml of penicillin and streptomycin, and 0.8 mg of G418/ml at 37°C: in a humidified atmosphere containing 5% CO 2 .
  • Cells are detached from T-175 flasks with a sterile solution containing 5mM EDTA in phosphate buffered saline. Cells are harvested by centrifugation and washed in RPMI media at 40°C for 5 minutes. The pellet is resuspended inTris-HCl (pH7.4) containing 1 uM phosphoramidon and 4 ug/ml of chymostatin at a cell density of 30 x 10 6 cells/ml. The suspension is then homogenized in a Brinkman Polytron (setting 5) for 30-45 seconds. The homogenate is centrifuged at 800 x g for 5 min at 4°C to collect unbroken cells and nuclei.
  • the supematant is centrifuged in a Sorvall RC5C at 19,000 rpm (44,00 x g) for 30 min at 4°C. The pellet is resuspended, an aliquot is removed for a protein determination (BCA) and washed again. The resulting pellet is stored at -80°C.
  • Binding is initiated by the addition of 100 ⁇ l of membrane (10-20 ⁇ g) containing the human NK-1 or NK-2 receptor in a final volume of 200 ⁇ l. After 40 minutes at room temperature, the reaction is stopped by rapid filtration onto Whatman GF/C filters which have been presoaked in 0.3% polyethylenimine. Filters are washed 2 times with 3 ml of 50 mM Tris-HCl (pH7.4). Filters are added to 6 mls of Ready-Safe liquid scintillation cocktail and quantified by liquid scintillation spectrometry in a LKB 1219 RackBeta counter.
  • Non-specific binding is determined by the addition of either 1 ⁇ M of CP-99994 (NK 1 ) or 1 ⁇ M SR-48968 (NK 2 ) (both synthesized by the chemistry department of Schering-Plough Research Institute).
  • IC 50 values are determined from competition binding curves and Ki values are determined according to Cheng and Prusoff using the experimentally determined value of 0.8 nM for the NK 1 receptor and 2.4 nM for the NK 2 receptor.
  • the NK 1 binding is in a range of about 0-100 % inhibition at 1 ⁇ M concentration.
  • the NK 2 binding is in a range of about 0-100 % inhibition at 1 ⁇ M concentration. It should be understood that while the NK binding for certain compounds of the invention is as low as 0% at 1 ⁇ M concentration, that at higher concentrations these compounds are expected to have NK binding inhibition activity.
  • the K i of a compound is that concentration at which the compound caused 50% inhibition of either NK 1 or NK 2 .
  • K i 's for NK 1 were determined.
  • the K i 's for NK 1 for such compounds fell within a range of about 0.1 nM to about 1 ⁇ M.
  • K i 's for NK 2 were determined.
  • the K i 's for NK 2 for such compounds fell within a range of about 0.1 nM to about 1 ⁇ M.
  • NK 1 and NK 2 antagonist activity exhibit NK 1 and NK 2 antagonist activity to varying degrees, i.e., certain compounds have strong NK 1 antagonist activity, but weaker NK 2 antagonist activity. Others are strong NK 2 antagonists, but weaker NK 1 antagonists. Certain compounds have both strong NK 1 and NK 2 antagonist activities. Some compounds can also be NK 3 antagonists.
  • One enantiomer can have different biological activity than the other.
  • one enantiomer can have strong NK 1 activity and weak NK 2 activity while the other enantiomer has weak NK 1 activity and strong NK 2 activity.
  • Certain compounds of the invention have been found to be antagonists of both NK 1 and NK 2 receptors, and are therefore useful In treating conditions caused or aggravated by the activity of NK 1 and NK 2 receptors.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • Compounds of this invention can be administered in conventional oral dosage forms such as capsules, tablets, powders, cachets, suspensions or solutions, or in injectable dosage forms such as solutions, suspensions, or powders for reconstitution.
  • the pharmaceutical compositions can be prepared with conventional excipients and additives, using well known formulation techniques.
  • Pharmaceutically acceptable excipients and additives include nontoxic and chemically compatible fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like.
  • the daily dose of a compound of the invention for treating asthma, cough, brohchospasm, inflammatory disease, migraine, nociception and gastrointestinal disorders is about 0.1 mg to about 20 mg/kg of body weight per day, preferably about 0.5 to about 15 mg/kg, more preferably 0.5 to about 5 mg/kg.
  • the dosage range is therefore from about 1 to about 1500 mg of drug per day, preferably about 50 to about 100 mg , given in a single dose or 2-4 divided doses.
  • the exact dose is determined by the attending clinician , and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.
  • Step 1 A solution of 2-(3,4-dichlorophenyl)piperazine (36.05 g, 0.156 mol) in CH 3 OH (200 mL) was treated with a solution containing two equivalents of N-acetyl-L-leucine (54.02 g, 0.312 mol) and heated until all of the material was dissolved. EtOAc (2.2 L) was added to this solution and allowed to stand at ambient temperature overnight. The solvent phase was decanted from the precipitated salt and concentrated in vacuo. This procedure was repeated using 37.88 g of 2-(3,4-dichlorophenyl)piperazine (0.164 mol) and 56.68 g of N-acetyl-L-leucine (0.327 mol).
  • Step 2 The concentrated salts from both solvent phases in step 1 were combined and heated in methanol (550 mL) until all of the material dissolved. EtOAc (2.75 L) was added to this solution and allowed to stand at ambient temperature overnight. The solvent phase was decanted from the precipitated salt and concentrated in vacuo to give ⁇ 95 g of piperazine salt (72% ee of enantiomer A).
  • Step 3 The salt from the solvent phase in step 2 was dissolved in a solution of H 2 O (800 mL) and aq. ammonia (400 mL) and extracted with CH 2 Cl 2 (4 x 400 mL). The combined organic layers were dried with MgSO 4 and concentrated to give 37 g of the piperazine free base.
  • Step 5 A 12.3 g portion of salt (75% ee of enantiomer B) prepared by an analogous procedure to that in step 4 was dissolved in 0.5 M NaOH (400 mL) and extracted with CH 2 Cl 2 (4 x 155 mL). The combined organic layers were dried with MgSO 4 and concentrated to give 3.72 g of the piperazine free base. The free base was recrystallized twice from hexane (90 and 70 mL) to give 2.1 g of piperazine (98% ee of enantiomer B).
  • the enantiomeric purity of the piperazine was measured by chiral HPLC analysis of the di-tert-butoxycarbonyl piperazine derivative.
  • the di-tert-butoxycarbonyl derivative was prepared by adding a small piperazine sample (free base or salt)( ⁇ .2 mg) to di-tert-butyl dicarbonate ( ⁇ 1 mg) and methanol (0.5 mL) and heating at 80°C for 1 h. If the piperazine sample is a salt, triethylamine (20 ⁇ L) is also added. The derivative was analyzed by HPLC using a ChiralPak AD column eluting with 95:5 hexane-isopropyl alcohol.
  • Step 1 To a solution of (+, -)-2-azabicyclo[2.2.1.]hept-5-en-3-one (3.9 g, 35.7 mmol) in DME (100 mL) at 0 °C was slowly added a1M solution of LAH/THF (180 mL, 180 mmol) under N 2 . After addition, the mixture was refluxed for 2 h then cooled to RT. Excess LAH was quenched slowly with saturated Na 2 SO 4 solution (50 mL) while keeping the reaction vessel under N 2 in a dry-ice acetone bath at -78 °C.
  • Step 2 To a suspension of compound 2 (3.93g, 29.8 mmol) (obtained from two batches) in CH 2 Cl 2 (40 mL) was added Hünig's base (5.6g, 29.8 mmol). To this solution of compound 2 was slowly added a solution of t-BOC anhydride (6.5 g, 29.8 mmol) in CH 2 Cl 2 (30 mL) at RT under N 2 .
  • Example 9 The compound obtained from Example 9 was separated on a YMC phenyl column, eluting with CH 3 OH:H 2 O:TFA (60:40:0.1%) with a flow rate of 0.8 mL / min. It was resolved into two compounds with retention times of 7.78 min (diastereomer A) and 9.35 min (diastereomer B). Both diastereomers are white solids after evaporating solvent.
  • Diastereomer B obtained from Example 10 was separated on a ChiralPak AD (Daicel) column, eluting with hexane:CH 3 OH:EtOH:Et 2 N (20:40:40:0.1), with a flow rate of 0.6 mL / min. It was resolved into two enantiomers with retention times of 10.97 min (enantiomer 1) and 12.49 min (enantiomer 2). Both enantiomers are solids after evaporating solvent.
  • Diastereomer A obtained from Example 10 was separated on a ChiralPak AD (Daicel) column, eluting with hexane:CH 3 OH:EtOH:Et 2 N (20:40:40:0.1), with a flow rate at 0.6 mL / min. It was resolved into two enantiomers with retention times of 14.91 min (enantiomer 3) and 17.98 min (enantiomer 4). Both enantiomers are white solids after evaporating solvent.
  • N-t-BOC-D-or L- amino acid derivatives of the product from Example 16 were prepared according to the method described in Example 17, using N-t-BOC-D-amino acids or N-t-BOC-L-amino acids in place of N-t-BOC-D-phenylglycine.
  • Example 19 The N-t-BOC-D-or L-amino acid derivatives listed in Example 19 were converted to the corresponding D- or L-amino acid derivatives according to the method described in Example 18.
  • N-t-butoxycarbonyl-4-piperidone 1 15 g, 75.3 mmol
  • pyridine 50 mL
  • hydroxylamine • HCl 5.23 g, 75.3 mmol
  • the mixture was heated in an oil bath at 65 °C for 1 h. After cooling, pyridine was removed under reduced pressure and the residue was dried under high vacuum overnight to give a solid.
  • water 100 mL
  • the precipitate was filtered and washed with water then dried under high vacuum to give the oxime derivative of compound 1 (10.5 g, 65%); FAB MS [M+1] + 215.3.
  • N-t-BOC-D-or L- amino acid derivatives of the product from Example 25 were prepared according to the methods described in Example 17, using the compound from Example 25 and N-t-BOC-D-amino acids or N-t-BOC-L- amino acids in place of N-t-BOC-D-phenylglycine.
  • Example 26 The N-t-BOC-D-or L-amino acid derivatives listed in Example 26 were converted to the corresponding D- or L-amino acid derivatives according to the method described in Example 18.
  • Step 1 To a solution of compound from Example 16 (1.0 g, 1.7 mmol) in CH 2 Cl 2 (100 mL) was added Hünig's base (0.621 mL, 3.57 mmol). After stirring at RT for 15 min, the reaction was diluted with CH 2 Cl 2 (100 mL), washed with brine (30 mL, 3x), dried (MgSO 4 ), filtered, and concentrated to give compound A (0.7 g, 11.9 mmol, 70%) as a white solid. Step 2 .
  • the title compound is prepared according to the scheme shown above by using the intramolecular 1,3-dipolar cycloaddition of nitrones to olefins (Chem. Comm., 874 (1984)) yielding polycyclic isovazolidines 1 and 2.
  • Compound 1 is converted to compound 3 by hydrogenation of compound 1 and protection of the nitrogen with t-BOC anhydride. Convert compound 3 to the title compound 9 using methods analogous to those described in Examples 6, 7, 8 and 9.
  • the title compound is prepared according to the scheme shown above by using the intramolecular 1 ,3-dipolar cycloaddition of nitrones to olefins (Chem. Comm., 874 (1984)) yielding polycyclic isovazolidines 1 and 2.
  • Compound 2 is converted to compound 3 by hydrogenation and protection of the nitrogen with t-BOC anhydride. Convert compound 3 to the title compound 9 using methods analogous to those described in Examples 6, 7, 8 and 9.
  • Example 39 To a solution of the product of Example 39 (129 mg, 0.195 mmol) in dry DMF (1.0 mL) at 0 °C was added 60% NaH (8.6 mg, 0.211 m mol). After stirring at 0 °C for 20 min, bromoacetonitrile (15 mL, 0.211 mmol) was added. After stirring at RT for 2 h, the reaction was quenched with water (2 mL). The mixture was diluted with EtOAc (200 mL) and extracted with brine (50 mL, 3x), dried (MgSO 4 ), filtered and evaporated to give a yellow solid.
  • Example 39 To a solution of the product of Example 39 (100 mg, 0.15 mmol) in DMF (1 mL) at 0 °C was added 60 % NaH in mineral oil (7.2 mg, 0.18 mmol). After stirring at 0 °C for 20 minutes, CH 3 l (11 ⁇ L, 0.18 mmol) was added and stirring was continued at 0 °C for 30 min. The reaction was diluted with EtOAc (100 mL) and washed with brine (30 mL, 2x), dried(MgSO 4 ), filtered and evaporated to give a solid.
  • Example 47 By an analogous method to that of Example 48, using endo compound prepared in Example 56 in place of exo compound (Example 47), the title compound was prepared as a solid, FAB MS [M+1] + 35 Cl 530.
  • Example 54 By analogous methods to those described in Examples 9, 49 and 50, using endo compound prepared in Example 57 in place of exo compound (Example 54), the following compounds were prepared as solids and purified by flash chromatography on silica gel.
  • step 3 To a solution of the product of step 3 (1.25g, 2.03 mmol) in CH 2 Cl 2 (2 mL) was added 4M HCl-dioxane solution (6 mL, 24 mmol). The mixture was stirred at RT for 2 h, then excess HCl was evaporated to give a yellow solid (1.2 g), FABMS 35 Cl[M+1] 515.1.
  • Example 65 The endo compound (3.6 g, 11.3 mmol) from Example 65 was dissolved in CH 3 OH (100 mL) and Pd(OH) 2 -C (0.76g) was added. The mixture was hydrogenolyzed at 45 psi at RT for 2 days. Additional Pd(OH) 2 -C (0.76g) was added and hydrogenolysis was continued at 45 psi for one more day.
  • Example 66 The title compound was prepared as its HCl salt according to the methods described in Example 66, but using the exo product made from Example 65 in place of the endo product from Example 65 with addition of HCl (0.5 equivalent) during the hydrogenolysis, FAB MS [M+1] + 227.0.

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Claims (9)

  1. Verbindung mit der Formel
    Figure imgb0330
     worin:
    y 1 bis 3 ist;
    jedes Ra und Rb unabhängig ausgewählt ist aus der Gruppe bestehend aus H, C1-C6-Alkyl, Phenyl, substituiertem Phenyl, Benzyl, substituiertem Benzyl und Allyl; oder wenn Ra und Rb an denselben Stickstoff gebunden sind, dann Ra und Rb zusammen mit dem Stickstoff, an den sie gebunden sind, einen 4- bis 7-gliedrigen Ring bilden können;
    jedes R1 und R2 unabhängig ausgewählt ist aus der Gruppe bestehend aus H, C1-C6-Alkyl, -CF3, -C2F5, Cl, Br, I, F, -NO2, -ORa, -CN, -NRaRb, -C(=O)Ra, -O-C(=O)-Ra, -O-C(=O)-N (RaRb), -N (Rb)-C (=O)-ORa, -N (Ra) -C(=O)-Rb, -C (=O)-ORa, -C(=O)-N(RaRb), -S(=O)-Ra, -SO2-Ra, -SRa und -SO2-NHRa, mit der Maßgabe, dass Ra in -S(=O)-Ra, -SO2-Ra oder -N(Rb)-C(=O)-ORa nicht H ist;
    oder wenn R1 und R2 an benachbarten Kohlenstoffen an einem Ring sind, können sie
    Figure imgb0331
     bilden, wobei n' 1 oder 2 ist;
    jedes R3 ist unabhängig ausgewählt aus der Gruppe bestehend aus H, C1-C6-Alkyl, -CF3, -C2F5, Cl, Br, I, F, -ORa, -OCF3, Phenyl, -C(=O)Ra, -O-C (=O)-Ra, -C (=O)-N (RaRb), -C(=X6)-N(RaRb) oder -N(Ra)-C(=X7)-N(RaRb');
    X6 =S oder =NR8 ist;
    Rb' Rb oder -ORb ist;
    R8 Rm, -ORm, -O-(CH2)n10-Rk oder -O(CH2)n11-Rn ist;
    Rm Ra oder Heteroaryl ist;
    Rk Rm, -ORm, -SO3H, -PO3H oder -N (RaRb) ist, und n10 2 bis 4 ist;
    Rn CN oder
    Figure imgb0332
     ist, und n11 1 bis 4 ist;
    X7 =O, =S, -NRa oder =N-ORa ist;
    Ar1 ist
    Figure imgb0333
     n4 ist 0 oder 1;
    Ar2 ist
    Figure imgb0334
     Z ist
    Figure imgb0335
    Figure imgb0336
     m1 und m2 unabhängig 0 oder 1 sind;
    m3 1, 2 oder 3 ist;
    n6 0 oder 2 ist;
    G ist
    Figure imgb0337
    Figure imgb0338
     n3 0 bis 4 ist;
    X8 -ORm, -SRm, Halogen, -O- (CH2)n10-Rk, -O- (CH2)n11-Rn, -S-(CH2)n10-Rk oder -S-(CH2)n11-Rn ist;
    Rg ist H, C1-C6-Alkoxy, C1-C6-Alkyl, C3-C8-Cycloalkyl, substituiertes C3-C8-Cycloalkyl, substituiertes Heterocycloalkyl, Heterocycloalkyl, Aryl, substituiertes Aryl, Heteroaryl, substituiertes Heteroaryl, -NRaRb, -O(CRaRb)n7-Aryl, -O-(CRaRb) -substituiertes Aryl, -O-(CRaRb)n7-Heteroaryl, -0- (CRaRb)n7-substituiertes Heteroaryl, NRa(CRaRb)n7-Heteroaryl, NRa(CRaRb)n7-substituiertes Heteroaryl, -O- (CRaRb)n7-Heterocycloalkyl, -O- (CRaRb)n7-substituiertes Heterocycloalkyl, -NRa- (CRaRb)n7-Aryl, -NRa- (CRaRb)n7-substituiertes Aryl, -NRa- (CRaRb)n7-Heterocycloalkyl oder -NRa-(CRaRb)n7-substituiertes Heterocycloalkyl;
    Rh ist H, C1-C6-Alkyl, -C(O)Ra, -C(O)NRaRb, -C(O)ORa, -C(O)CH (N (Ra)(Rb))-R7, -SO2Rm, - (CH2)n10-Rk, -(CH2)n11-Rn, -C(=NRa)-N (RaRb) oder -N (=NORa)-N (RaRb), mit der Maßgabe, dass, wenn Rh -C(O)ORa ist, Ra nicht H ist;
    R1 ist -CN oder -Ra;
    n7 ist 0 bis 4;
    jedes Re und Rf ist H;
    n5 ist 1 bis 2;
    jedes R5 ist H oder C1-C6-Alkyl;
    R6 ist H, C1-C6-Alkyl, C3-C8-Cycloalkyl, substituiertes C3-C8-Cycloalkyl, Heteroaryl, substituiertes Heteroaryl, Heterocycloalkyl, substituiertes Heterocycloalkyl,
    Figure imgb0339
     wobei X3 nicht (H,H) ist, wenn
    n3 1 ist,
    Figure imgb0340
    Figure imgb0341
     X3 ist (H,H), =O, =NRd oder =S;
    n8 ist 0, 1 oder 2; n9 ist 1 oder 2;
    R7 ist
    Figure imgb0342
     mit der Maßgabe, dass wenn Z
    Figure imgb0343
     ist und die Summe von m1 plus m2 1 oder 2 ist, G nicht
    Figure imgb0344
     ist, mit der Maßgabe, wenn Z
    Figure imgb0345
     ist,
    und wenn m1 0 oder 1 ist und m2 O ist, G nicht
    Figure imgb0346
     ist;
    wenn R3 H, C1-C6-Alkyl, -CF3, -C2F5, Cl, Br, I, F, -ORa, -OCF3, Phenyl, -C(=O)-Ra, -O-C(=O)-Ra oder -C(=O)-N(RaRb) ist; und mit der Maßgabe, dass, wenn Z
    Figure imgb0347
     ist, G nicht
    Figure imgb0348
     oder
    Figure imgb0349
     ist;
    oder irgendein Enantiomer oder Diastereomer davon,
    oder ein pharmazeutisch annehmbares Salz davon,
    wobei substituiertes Phenyl, substituiertes Benzyl, substituiertes Aryl und substituiertes Heteroaryl Phenyl, Benzyl, Aryl und Heteroaryl bedeuten, das mit R1, R2 und/oder R3 wie oben definiert substituiert ist;
    Aryl Phenyl, Naphthyl, Indenyl, Tetrahydronaphthyl, Indanyl, Anthracenyl oder Fluorenyl bedeutet und
    Heterocycloalkyl einen 4- bis 6-gliedrigen Ring bedeutet, der 1 bis 3 Heteroatome unabhängig ausgewählt aus der Gruppe bestehend aus -O-, -S- und -N(R6)- enthält, wobei die restlichen Ringglieder Kohlenstoff sind, und
    Heteroaryl einen 5- bis 10-gliedrigen einzelnen oder benzokondensierten Ring bedeutet, der 1 bis 3 Heteroatome unabhängig ausgewählt aus der Gruppe bestehend aus -O-, -S- und -N= enthält.
  2. Verbindung nach Anspruch 1, wobei Re oder Rf H ist und R6
    Figure imgb0350
    Figure imgb0351
     wobei X3 nicht (H,H) ist, wenn n3 1 ist,
    Figure imgb0352
     ist.
  3. Verbindung nach einem der Ansprüche 1 oder 2, worin Rg
    Figure imgb0353
     ist, wobei Ra nicht H ist,
    Figure imgb0354
    Figure imgb0355
    Figure imgb0356
     ist.
  4. Verbindung ausgewählt aus der Gruppe bestehend aus Verbindungen mit der Formel
    Figure imgb0357
     wobei G' ausgewählt ist aus der Gruppe bestehend aus:
    Figure imgb0358
    Figure imgb0359
    Figure imgb0360
    Figure imgb0361
    Figure imgb0362
    Figure imgb0363
    Figure imgb0364
    Figure imgb0365
     Verbindungen mit den Formeln
    Figure imgb0366
    Figure imgb0367
    Figure imgb0368
    Figure imgb0369
     wobei G" und G"' ausgewählt sind aus der Gruppe bestehend aus:
    Figure imgb0370
     wobei R6, ausgewählt ist aus der Gruppe bestehend aus
    Figure imgb0371
    Figure imgb0372
     oder G" und G"' ausgewählt sind aus der Gruppe bestehend aus:
    Figure imgb0373
    Figure imgb0374
     wobei Rm' ausgewählt ist der Gruppe bestehend aus
    Figure imgb0375
     und wobei G" auch ausgewählt ist aus der Gruppe bestehend aus
    Figure imgb0376
    Figure imgb0377
     und wobei G"' auch ausgewählt ist aus der Gruppe bestehend aus
    Figure imgb0378
     und Verbindungen mit der Formel
    Figure imgb0379
    Figure imgb0380
    Figure imgb0381
    Figure imgb0382
    Figure imgb0383
    Figure imgb0384
    Figure imgb0385
     wobei R6' wie oben definiert ist und Ar' ausgewählt ist aus der Gruppe bestehend aus
    Figure imgb0386
     oder irgendwelchem Stereoisomer davon einschließlich irgendeines Enantiomers, Diastereomers, endo, exo, irgendeiner R- oder S-Form davon, oder einem pharmazeutisch annehmbaren Salz davon.
  5. Verbindung ausgewählt aus der Gruppe bestehend aus Verbindungen, die durch die Formel
    Figure imgb0387
     wiedergegeben werden, worin Ga ausgewählt ist aus der Gruppe bestehend aus
    Figure imgb0388
    Figure imgb0389
    Figure imgb0390
    Figure imgb0391
     Verbindungen mit der Formel
    Figure imgb0392
     wobei Gc ausgewählt ist aus der Gruppe bestehend aus:
    Figure imgb0393
     und Verbindungen, die durch die Formel
    Figure imgb0394
     wiedergegeben werden, wobei Gc wie oben definiert ist.
  6. Pharmazeutische Zusammensetzung, die eine als Neürokininantagonist wirksame Menge einer Verbindung nach einem der Ansprüche 1 bis 5 und ein pharmazeutisch annehmbares Trägermaterial enthält.
  7. Verwendung einer Verbindung nach einem der Ansprüche 1 bis 5 zur Herstellung eines Medikaments zum Induzieren von Neurokininantagonismus.
  8. Verwendung einer Verbindung nach einem der Ansprüche 1 bis 5 zur Herstellung eines Medikaments zur Behandlung von Lungenerkrankungen; Hauterkrankungen oder Juckreiz; neurogenen entzündlichen Erkrankungen; Erkrankungen des zentralen Nervensystems; Down-Syndrom; Neuropathie; multipler Sklerose; ophthalmischen Erkrankungen; Konjunktivitis; Autoimmunerkrankungen; Transplantatabstoßung; systemischem Lupus erythematosus; Gastrointestinalerkrankungen; Störungen der Blasenfunktion; Kreislauferkrankungen; Morbus Raynaud; Husten oder Schmerz.
  9. Verfahren zur Herstellung einer pharmazeutischen Zusammensetzung wie in Anspruch 6 definiert, bei dem eine Verbindung nach einem der Ansprüche 1 bis 5 mit einem pharmazeutisch annehmbaren Träger gemischt wird.
EP97912827A 1996-10-30 1997-10-28 Piperazinoderivate als neurokinin-antagonisten Expired - Lifetime EP0937069B1 (de)

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SE9904765D0 (sv) 1999-12-23 1999-12-23 Astra Ab Pharmaceutically-useful compounds
WO2002024680A1 (en) 2000-09-21 2002-03-28 Smithkline Beecham P.L.C. Imidazole derivatives as raf kinase inhibitors
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